Nitrogen mustards are cytotoxic chemotherapy agents for the treatment of various diseases, such as neoplastic diseases and autoimmune diseases. Because of their high reactivity in an aqueous solution, nitrogen mustards are difficult to formulate as pharmaceuticals and are often supplied for administration in a lyophilized form that requires reconstitution by skilled hospital personnel prior to administration. Nitrogen mustards are prone to degradation in an aqueous solution. Thus, after reconstitution, the product should be promptly administered to a patient,
Carmustine is one species of nitrogen mustards. Specifically, it is a β-chloro-nitrosourea compound useful in chemotherapy of certain neoplastic diseases. Carmustine has the chemical name: 1,3-bis (2-chloroethyl)-1-nitrosourea, with a molecular weight of 214.06 and the following structure (Formula I):

Carmustine is also called a dialkylating agent because it may provide two alkylating groups. It is very soluble in alcohol, such as tertiary butanol (also known as 2-methylpropan-2-ol, tert-butanol, t-butanol, t-butyl alcohol, or TBA), dichloromethane, and ether, and slightly soluble in water with a solubility of 4 mg/mL. Carmustine readily gets hydrolyzed in water at pH>6. Carmustine has a Log P value of 1.53. Its antineoplastic activity is mainly due to its effect on DNA, RNA, mitochondrial glutathion reductase and Cytochrome P450 enzyme.
Carmustine is commercially available as a sterile lyophilized powder for injection under the tradename BiCNU®. BiCNU® (carmustine for injection) is indicated for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin lymphoma (NHL). The lyophilized dosage formulation of carmustine typically contains no preservatives and is not intended for use as a multiple dose vial. BiCNU® (carmustine for injection) is available in single dose vials containing 100 mg of lyophilized powders of carmustine in each vial. Sterile diluent for constitution of BiCNU® (carmustine for injection) is co-packaged with the active drug product (i.e., lyophilized carmustine) for use in constitution of the lyophilsate. The lyophilized carmustine appears as pale yellow dry flakes or dry congealed mass. Prior to injection, the lyophilized carmustine is reconstituted with a diluent with ethanol and the solution is further diluted with water. The reconstitution results in a clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, USP.
Camustine has a low melting point of 30.5° C. to 32.0° C., exposure of carmustine to this temperature or above will cause the drug to liquefy and appear as an oil film on the vials. This may be a sign of decomposition and vials may need to be discarded. For this reason, carmustine is it is typically stored at 2-8° C. in a sealed vial. Unopened BiCNU® vials may provide a stable product for up to 3 years. After reconstitution, BiCNU® is stable for 24 hours under refrigeration at 2-8° C. Reconstituted vials should be examined for crystal formation prior to use. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation.
The preparations of carmustine, its pharmaceutically acceptable salts, and/or compositions thereof, have been disclosed in the prior art. For example, Flamberg et al. discloses a low temperature vacuum drying process for preparing sterile carmustine from an ethanol solution, in which ethanol is the only solvent. (Flamberg et al., Low temperature vacuum drying of sterile parenterals from ethanol, Bulletin of Parenteral Drug Assoc. 1970 Sep.-Oct. 24 (5):209-17). The nature of the product described in this publication is very similar to what is currently on the market as a commercial product, BiCNU®.
One issue in the manufacturing process of the commercial product BiCNU® is that lyophilized carmustine deposited in a glass container tends to reach up to the neck of a glass container. As a result, there is a risk for drug exposure to operators, potential loss of product, and potential loss of potency in the lyophilization chamber. The commercial product BiCNU® may also show undesirable signs of particulate matter, signs of melting or liquidification present in the product.
There is a need for an improved, robust carmustine formulating process. There is also a need for a lyophilized formulation of carmustine which produces better quality powder cakes, improved stabilities, and improved impurity profiles than the lyophilized powder of carmustine currently on the market.